Reactive oxygen species in Alzheimer's disease: studies of amyloid-beta-copper and apolipoprotein E
File(s)
Author(s)
Girvan, Paul
Type
Thesis
Abstract
There are many hypotheses for the cause of Alzheimer’s disease. This thesis explores
one such hypothesis, the metals hypothesis, and attempts to do so from a kinetic
point of view. The metals hypothesis posits that Amyloid-b (Ab) can bind intrinsic
metals within the brain, causing increased Ab oligomerisation, and (in the case of
binding copper or iron) is able to be a source of reactive oxygen species (ROS), via
redox cycling of the Ab-metal complex.
In the first part of this thesis I draw comparisons between wild-type Ab and
disease prone mutants, providing evidence that the disease mutants have 50%
higher copper assisted dimerisation rate constants, compared to the wild-type Ab. In
doing so I try to highlight the beneficial insights that a kinetic understand can afford.
I explore the kinetic mechanism of AbCu redox cycling, attempting to address on
what timescale the process occurs. I show that the reduction step is fairly rapid
(tens of millisecond timescale), and follows a conformational selection mechanism.
But that redox cycling is ultimately limited by the relatively slow oxidation.
Looking further at the role of AbCu in ROS generation, I shown that AbCu is
almost twice as efficient at causing lipid membrane peroxidation than uncomplexed
Cu. This increased efficiency is surprising considering uncomplexed Cu can generate
ROS much more rapidly than AbCu.
Finally, this thesis moves on to look at apolipoprotein E (apoE), which is the
biggest genetic risk factor for developing late onset AD. I explore the role of apoE as
a lipoprotein and show that it displays antioxidant effects, protecting against lipid
peroxidation.
one such hypothesis, the metals hypothesis, and attempts to do so from a kinetic
point of view. The metals hypothesis posits that Amyloid-b (Ab) can bind intrinsic
metals within the brain, causing increased Ab oligomerisation, and (in the case of
binding copper or iron) is able to be a source of reactive oxygen species (ROS), via
redox cycling of the Ab-metal complex.
In the first part of this thesis I draw comparisons between wild-type Ab and
disease prone mutants, providing evidence that the disease mutants have 50%
higher copper assisted dimerisation rate constants, compared to the wild-type Ab. In
doing so I try to highlight the beneficial insights that a kinetic understand can afford.
I explore the kinetic mechanism of AbCu redox cycling, attempting to address on
what timescale the process occurs. I show that the reduction step is fairly rapid
(tens of millisecond timescale), and follows a conformational selection mechanism.
But that redox cycling is ultimately limited by the relatively slow oxidation.
Looking further at the role of AbCu in ROS generation, I shown that AbCu is
almost twice as efficient at causing lipid membrane peroxidation than uncomplexed
Cu. This increased efficiency is surprising considering uncomplexed Cu can generate
ROS much more rapidly than AbCu.
Finally, this thesis moves on to look at apolipoprotein E (apoE), which is the
biggest genetic risk factor for developing late onset AD. I explore the role of apoE as
a lipoprotein and show that it displays antioxidant effects, protecting against lipid
peroxidation.
Version
Open Access
Date Issued
2018-09
Date Awarded
2019-02
Copyright Statement
Creative Commons Attribution NonCommercial No Derivatives Licence
Advisor
Ying, Liming
Baldwin, Geoff
Brooks, Nick
Barahona, Mauricio
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)